The current proposal is based on the premise that the genetic architecture of many common diseases will only be defined by a "genomic" approach that incorporates high throughput technologies and considers higher order effects (i.e., interactions involving multiple genes and/or environmental exposures). The proposed activities are motivated by the desires of the investigators to integrate their current molecular epidemiological approaches to the study of birth defects and cancer, and to expand their efforts to encompass a genomic approach to the study of pharmacological agents as risk factors for these conditions. These activities will build on methodological issues, pharmacological agents (e.g., folate antagonists) and genetic pathways (e.g., folate-homocysteine metabolic axis) that are common to birth defects and cancer. The successful expansion of research efforts to encompass a genomics approach will require expertise from multiple disciplines which traditionally have not been well integrated. Hence, funding for the proposed project will be used to establish, at the University of Pennsylvania School of Medicine (PENN), a research team that has the scientific expertise and technological resources required to undertake a genomic approach to the study of disease etiology. The tools and resources developed by this team will provide the foundation for future "genome-based" studies of pharmacological agents as risk factors for birth defects and cancer. In addition, since many of the tools and resources that are required of a genomic approach are neither disease- nor exposure- specific, the work of this team will also serve to foster, at PENN, genomic research on many additional environmentally-induced diseases.